PROJECT SUMMARY The long-term goal of this proposal is to apply the Human Connectome Project (HCP) data collection protocol and develop robust technology to accurately stage Alzheimer's disease (AD) across the full spectrum of its progression on an individual subject basis. The onset of AD is insidious, and significant irreversible brain damage is already present by the time clinical symptoms appear. One difficulty in the field of AD research is that we have not yet established firm links between the appearance of any specific biomarker in asymptomatic individuals and the subsequent emergence of clinical symptoms. In this proposed study, we will utilize the HCP approach to determine when, where, and how the dysfunctional networks occur during disease development, and establish links by integrating HCP connectome biomarkers with well-studied molecular, genetic, and cognitive biomarkers to stage preclinical AD risks and subsequent AD progression. The success of the proposed project will open a crucial window of opportunity to intervene with disease-modifying therapy. Specifically, we hypothesize that HCP connectome biomarkers can predict and stage the full spectrum of AD dementia from the preclinical phase to dementia onset using a novel event-based probabilistic model on an individual subject basis. To test this hypothesis, we will conduct the following four aims. Aim 1. HCP compatibility. We will implement the HCP LifeSpan protocols with additional anatomical, functional, and positron emission tomography (PET) sequences tailored for aging and AD. Aim 2. Aberrant connectivity in AD. We will acquire and quantitatively characterize the connectome biomarkers in the AD connectome project (ADCP) cohort and determine their individual stages in AD progression. Aim 3. We will measure longitudinal changes in brain connectome, diseases stage development, and cognitive changes in the ADCP cohort and prospectively validate the probability distribution of biomarker-based AD stages on an individual subject basis using Markov chain estimation. Aim 4. Determine the extent to which connectome biomarkers are predicted by amyloid (A?) and tau pathologies. The completion of this Aim 4 will shed light on the molecular neurobiology of connectivity dysfunction and clarify the pathophysiology of AD development. This study will have significant impact to transform AD research paradigms in three ways. It will 1) allow for selection of individuals at high risk in order to enrich clinical trials, 2) identify the earliest preclinical disease stage at the individual subject level, and 3) be a critical step toward the goal of developing personalized medicine for AD prevention and treatment.